Hypertrophic cardiomyopathy and mitral valve prolapse are both conditions that may be genetically transmitted and also incur a risk for sudden cardiac death. While the distorted ventricular geometry in hypertrophic cardiomyopathy might suggest a predisposition to mitral valve prolapse, the frequency with which the two entities coexist is not known, nor is the clinical significance of such an association. To further define the relationship of hypertrophic cardiomyopathy to mitral valve prolapse, 529 consecutive patients with hypertrophic cardiomyopathy were studied by echocardiography. Unequivocal systolic prolapse into the left atrium was identified in only 16 (3%) of the 529 patients. Of these 16 patients, 8 also had systolic anterior motion (including 5 with mitral-septal contact and basal outflow obstruction); 10 of the 16 had evidence of substantial mitral regurgitation. Of note, 9 of the 16 patients with hypertrophic cardiomyopathy and mitral valve prolapse had experienced atrial fibrillation associated with marked left atrial enlargement compared to 75 of 513 patients with hypertrophic cardiomyopathy but without prolapse. Hence, in a large population of patients with hypertrophic cardiomyopathy, prevalence of mitral prolapse was relatively low. This frequency of mitral valve prolapse would appear less than expected, based on the reported prevalence of mitral valve prolapse and hypertrophic cardiomyopathy individually in the general population. However, those patients in whom hypertrophic cardiomyopathy and mitral valve prolapse coexist appear to develop atrial fibrillation with greater frequency than the general population of hypertrophic cardiomyopathy. These data provide a mechanism by which to prospectively identify some patients with hypertrophic cardiomyopathy who are predisposed to develop atrial fibrillation.